Mg Of Moxifloxacin Research Articles

Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for α4-integrin antagonist carotegrast methyl in Japanese healthy subjects

We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, carotegrast methyl hardly altered ΔQTcF and ΔΔQTcF with the largest mean values of 0.8 ms (−2.3, 3.9) and 2.1 ms (−0.7, 4.8) for the low dose, and −0.2 ms (−3.4, 3.0) and 1.6 ms (−0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean Cmax, whereas carotegrast methyl provided those of −4.6 ms (−7.3, −1.9) and 0.7 ms (−1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As.

Four-Way Crossover Phase 1 Thorough QT Study to Assess Cardiac Safety of Domperidone and Consideration for Design and Conduct of QT/QTc Study in China.

This study aimed to evaluate the QT prolongation potential of domperidone in healthy Chinese participants and explore the possibility of a thorough QT (TQT) study in China with a smaller sample size using concentration-QT (C-QT) modeling. Part 1 was a randomized, placebo- and positive-controlled, multiple-dose, 4-way crossover TQT study in healthy Chinese participants; 44 participants were randomized to either domperidone 10/20mg or placebo 3 times daily, on days 1 to 3, followed by a single dose of either 10/20mg domperidone/domperidone-placebo/domperidone-placebo plus 400mg of moxifloxacin, on day 4. Twelve-lead electrocardiograms were recorded in triplicate at predefined time points with pharmacokinetic sampling. The results were that change from baseline in QT interval corrected for heart rate (QTc) using the Fridericia formula (QTcF) between domperidone and placebo was 1.3milliseconds and 2.7milliseconds for 10 and 20mg 3 times daily, and upper limits of 2-sided 90%CI for all time points were below regulatory threshold of 10milliseconds. In part 2, resampling analysis using C-QT modeling for moxifloxacin showed false-negative rates of <5% with sample sizes ≥6. We could conclude that no clinically relevant effect on corrected QT interval or new safety signals was observed with domperidone. A dedicated TQT study with C-QT modeling could assess drug effects on QT/corrected QT intervals for novel drug development in China.

Moxifloxacin Concentrations in the Knee Joint, Tibial Bone, and Soft Tissue When Combined with Rifampicin: A Randomized Porcine Microdialysis Study.

Peri and postoperative antibiotics are key adjuvant treatment tools in the management of periprosthetic joint infection (PJI). The aim of this study was to evaluate the effect of rifampicin on the area under the moxifloxacin concentration-time curve from 0 to 24 hours (AUC0-24) in the synovial fluid of the knee joint, tibial bone, and adjacent subcutaneous tissue under steady-state conditions using microdialysis in a porcine model. Twenty female pigs were randomized to receive oral treatment with moxifloxacin monotherapy (Group A, n = 10) of 400 mg once daily for 3 days or a combination therapy (Group B, n = 10) of 400 mg of moxifloxacin once daily for 3 days and 450 mg of rifampicin twice daily for 7 days. Microdialysis was used for sampling the synovial fluid of the knee joint, tibial cancellous and cortical bone, and adjacent subcutaneous tissues. Plasma samples were taken as a reference. Measurements were obtained for 24 hours. Coadministration of moxifloxacin and rifampicin resulted in reductions of the moxifloxacin AUC0-24 in all targeted tissue compartments by 67% to 85% (p < 0.05). The corresponding change in plasma was 20% (p = 0.49). For both groups, the tissue penetration (the ratio of tissue free fraction AUC0-24 to plasma free fraction AUC0-24 [fAUCtissue/fAUCplasma]) was incomplete in all investigated compartments. The highest moxifloxacin tissue penetration was in the knee joint synovial fluid: 0.59 (Group A) and 0.24 (Group B). The lowest tissue penetration was in the cortical bone: 0.17 (Group A) and 0.03 (Group B). We found a significant reduction of the moxifloxacin concentration, expressed as the AUC0-24, in tissues relevant to acute PJI treatment when coadministered with rifampicin. The concentrations within the targeted tissue compartments were reduced significantly more than the concentrations in plasma, which may be particularly important as plasma concentrations are used in clinical practice to assess moxifloxacin treatment sufficiency.

OUP accepted manuscript

Pyogenic spondylodiscitis remains a therapeutic challenge, as demonstrated by divergent treatment guidelines. The combination of moxifloxacin and rifampicin may be an attractive treatment option for cases caused by staphylococci; however, previous studies have reported a reduction in plasma concentrations of moxifloxacin when coadministered with rifampicin. The magnitude of this reduction in spinal tissues is not known. To investigate the effect of rifampicin on moxifloxacin tissue concentrations in vertebral cancellous bone, the intervertebral disc and subcutaneous adipose tissue under steady-state conditions using microdialysis in a porcine model. Twenty female pigs were randomized into two groups of 10 pigs. Group A received 400 mg of moxifloxacin orally once daily for 3 days preoperatively. Group B received 400 mg of moxifloxacin orally once daily for 3 days preoperatively combined with 450 mg of rifampicin twice daily for 7 days preoperatively. Measurements were obtained from plasma, vertebral cancellous bone, the intervertebral disc and subcutaneous adipose tissue for 24 h. Microdialysis was applied for sampling in solid tissues. Coadministration of moxifloxacin and rifampicin demonstrated a reduction of free moxifloxacin concentrations in spinal tissues. Cmax and AUC0-24 in all tissue compartments decreased in the ranges of 66%-79% and 65%-76%, respectively. Using microdialysis, we demonstrated a significant reduction of moxifloxacin Cmax and AUC0-24 in the spinal tissues when coadministered with rifampicin.

Repeated determination of moxifloxacin concentrations in interstitial space fluid of muscle and subcutis in septic patients.

For an effective antimicrobial treatment, it is crucial that antibiotics reach sufficient concentrations in plasma and tissue. Currently no data exist regarding moxifloxacin plasma concentrations and exposure levels in tissue under septic conditions. To determine the pharmacokinetics of moxifloxacin in plasma and interstitial space fluid over a prolonged period. Ten septic patients were treated with 400 mg of moxifloxacin once a day; on days 1, 3 and 5 of treatment plasma sampling and microdialysis in the subcutis and muscle of the upper thigh were performed to determine concentrations of moxifloxacin in different compartments. This trial was registered in the German Clinical Trials Register (DRKS, register number DRKS00012985). Mean unbound fraction of moxifloxacin in plasma was 85.5±3.4%. On day 1, Cmax in subcutis and muscle was 2.8±1.8 and 2.5±1.3 mg/L, respectively, AUC was 24.8±15.1 and 21.3±10.5 mg·h/L, respectively, and fAUC0-24/MIC was 100.9±62.9 and 86.5±38.3 h, respectively. Cmax for unbound moxifloxacin in plasma was 3.5±0.9 mg/L, AUC was 23.5±7.5 mg·h/L and fAUC0-24/MIC was 91.6±24.8 h. Key pharmacokinetic parameters on days 3 and 5 showed no significant differences. Clearance was higher than in healthy adults, but tissue concentrations were comparable, most likely due to a lower protein binding. Surprisingly, the first dose already achieved exposure comparable to steady-state conditions. The approved daily dose of 400 mg was adequate in our patient population. Thus, it seems that in septic patients a loading dose on the first day of treatment with moxifloxacin is not required.

QTc prolongation with energy drinks comparable to moxifloxacin

Energy drinks have been linked to an increase in emergency room visits and death. Several studies have evaluated the QT/correct QT (QTc) interval changes post high volume energy drink consumption but report discordant data. We report a case of a 26 year old healthy female who voluntarily consumed 400 mg of moxifloxacin with 32 oz of a control drink (active-control), 32 oz of a caffeinated energy drink, 32 oz of a control drink (placebo-control) on 3 separate days. A standard 12‑lead electrocardiogram (ECG) was performed at approximately the same time of day on 3 separate occasions at baseline, 1, 2, 4 and 6 h post-consumption. The maximum post-dosing QTc in the moxifloxacin (QTc = 438), and 32 oz energy drink (QTc = 441) were higher than the placebo (QTc = 428). These results need to be replicated in larger studies using robust methodologies before considering labelling or public health implications.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 μg/mL) and a mean slope ranging from 2.33 to 2.96 ms per μg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis.

Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500-750 mg of cycloserine QD, 4.95-6.6 g of PAS twice daily and 750-1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.

Aqueous penetration of orally and topically administered moxifloxacin.

To assess the intraocular penetration of 0.5% moxifloxacin hydrochloride into aqueous humour after oral and topical administration. A prospective, interventional study of 42 patients scheduled to undergo cataract surgery was carried out. Out of the 42 subjects, 21 were randomly categorised into Group I and received one drop of 0.5% topical moxifloxacin four times, at 15 min intervals starting 75 min before the surgery. Another 21 subjects were categorised into Group II and all subjects in this group were administered a single tablet of 400 mg of moxifloxacin, 12 h before the surgery. Estimation of moxifloxacin in aqueous samples was carried out using high-performance liquid chromatography. Results were analysed using Student unpaired 't' test and analysis of variance. The value of p<0.05 was considered to be significant. Mean aqueous concentration of moxifloxacin attained in the oral group (n=21) was 0.504±0.30 μg/mL while that in the topical group (n=21) was 2.04±0.72 μg/mL, and this difference in levels was statistically significant (p<0.005). The levels attained by both the groups well exceeded the MIC90 (minimum inhibitory concentration of antibiotic required to inhibit growth of 90% of bacteria strains) levels for most of the organisms causing endophthalmitis. Penetration of moxifloxacin in aqueous in both the groups was not affected by gender, intraocular pressure or comorbidities significantly. However, aqueous levels were found to be higher among the younger subjects within the topical group. Moxifloxacin has an impressive spectrum of coverage and this pharmacokinetic study reinforces its potential as a prophylactic drug against intraocular infections, given the high aqueous levels post topical administration.

Pharmacokinetic-pharmacodynamic analysis to evaluate the effect of moxifloxacin on QT interval prolongation in healthy Korean male subjects.

A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.

Comparative roles of moxifloxacin and levofloxacin in the treatment of pulmonary multidrug-resistant tuberculosis: a retrospective study

This study compared the efficacy of moxifloxacin and levofloxacin in the treatment of multidrug-resistant tuberculosis (MDR-TB) in Shanghai, China. A retrospective analysis of 158 patients with MDR-TB receiving either moxifloxacin- or levofloxacin-containing regimens was performed. Clinical data from patients were subjected to univariate analysis, stratification and multiple logistic regression to compare the roles of moxifloxacin and levofloxacin in multidrug regimens. In total, 72 patients received 400mg of moxifloxacin once daily and 86 patients received 509.9±79.4mg (mean±standard deviation) of levofloxacin once daily together with similar active agents for similar durations. The times to sputum culture conversion were similar. Adverse reactions occurred at comparable rates. The combined treatment success rate was 60.1%, being higher among ofloxacin-susceptible than ofloxacin-resistant cases (67.5% vs. 52.0%; P<0.05). The success rates for the moxifloxacin group were 65.3% (overall), 77.1% (ofloxacin-susceptible cases) and 54.1% (ofloxacin-resistant cases) in comparison with 55.8%, 60.4% and 50.0%, respectively, for the levofloxacin group. No demographic, clinical, bacteriological or treatment characteristics were independent predictors of favourable outcome. Fourteen patients from the moxifloxacin group and twelve patients from the levofloxacin group had bacteriological relapse after treatment cessation. In conclusion, compared with levofloxacin, moxifloxacin did not show superior efficacy when incorporated into multidrug regimens used for the treatment of MDR-TB.

Daily Dosing of Vismodegib to Steady State Does Not Prolong the Qtc Interval in Healthy Volunteers

Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval. Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in ΔQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/μM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in ΔQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity. There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.

The effect of the molecular adsorbent recirculating system on moxifloxacin and meropenem plasma levels

Adequate plasma antibiotic concentrations are necessary for effective elimination of invading microorganism; however, extracorporeal organ support systems are well known to alter plasma concentrations of antibiotics, requiring dose adjustments to achieve effective minimal inhibitory concentrations in the patient's blood. A mock molecular adsorbent recirculating system (MARS) circuit was set using 5000 ml of bovine heparinized whole blood to simulate an 8-h MARS treatment session. After the loading dose of 400 mg of moxifloxacin or 2 g of meropenem had been added, blood was drawn from the different parts of the MARS circuit at various time points and analyzed by high-performance liquid chromatography. The experiments were performed in triplicate. Additionally, meropenem concentrations were determined in the plasma of one patient treated with MARS suffering from acute liver failure due to an idiosyncratic reaction to immunosuppressive medication. In our single-compartment model, a significant decrease in the quasi-systemic concentration of moxifloxacin and meropenem could be detected as early as 15 min after the commencing of the MARS circuit. Moreover, within 60 min the moxifloxacin and meropenem concentrations were less than 50% of the initial value. The activated charcoal removed the majority of moxifloxacin and meropenem in the albumin circuit. In our patient, the meropenem concentrations in the return line after MARS were constantly lower than in the access line, indicating a likely removal of meropenem through MARS. Our data provide evidence that moxifloxacin and meropenem are effectively removed from the patient's blood by MARS, leading to low plasma levels. Dose adjustments of both antibiotic compounds may be required.

Shortening of the QT Interval After Food Can Be Used to Demonstrate Assay Sensitivity in Thorough QT Studies

The effect of food was investigated under conditions of a thorough QT (TQT) study and with confirmation of assay sensitivity by the use of a positive control (400 mg of moxifloxacin). Fifty-five healthy subjects were randomized to treatment and a sequence of fasted and fed baseline electrocardiography days. Subjects received standard breakfast 30 to 10 minutes prior to dosing. Measurement of QT interval was performed automatically with subsequent manual onscreen overreading using electronic calipers. A profound increase in heart rate of 9.4 bpm was observed in the fed condition compared with the fasted condition at 1.5 hours after dose with a corresponding shortening of QT (27 milliseconds); (baseline data). When corrected, QTcF interval was shortened significantly with the maximal effect observed at 2 hours after dose of 8.2 (95% confidence interval, 6-10) milliseconds. A concurrent shortening of the PR interval with a maximum value of 5.6 milliseconds was also observed. The findings of this study demonstrate that food alters the QT-RR relationship and shortens QTc and PR for at least 4 hours after a carbohydrate-rich meal. The findings are of regulatory interest as this study shows that normal physiological causes can shorten QTc significantly and that it could be used as a method to demonstrate assay sensitivity.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery

Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg · h/L after oral dosing and 52.3 ± 1.3 mg · h/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

A randomized trial of the efficacy and safety of sequential intravenous/oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections

ObjectivesThe primary aim of the RELIEF study was to evaluate the efficacy and safety of two sequential intravenous (iv)/oral regimens: moxifloxacin iv/oral versus piperacillin/tazobactam (TZP) iv followed by oral amoxicillin/clavulanate (AMC).Patients and methodsThe study had a prospective, randomized, double-dummy, double-blind, multicentre design. Patients ≥18 years were prospectively stratified according to complicated skin and skin structure infection (cSSSI) subtype/diagnosis (major abscess, diabetic foot infection, wound infection or infected ischaemic ulcer), surgical intervention and severity of illness. Diagnoses and disease severity were based on predetermined criteria, documented by repeated photographs, and confirmed by an independent data review committee. Patients were randomized to receive either 400 mg of moxifloxacin iv once daily followed by 400 mg of moxifloxacin orally once daily or 4.0/0.5 g of TZP iv thrice daily followed by 875/125 mg of AMC orally twice daily for 7–21 days. The primary efficacy variable was clinical response at test of cure (TOC) for the per-protocol (PP) population. Clinical efficacy was assessed by the data review committee based on repeated photographs and case descriptions. Clinical trials registry number: NCT 00402727.ResultsA total of 813 patients were randomized. Clinical success rates at TOC were similar for moxifloxacin and TZP–AMC in the PP [320/361 (88.6%) versus 275/307 (89.6%), respectively; P = 0.758] and intent-to-treat (ITT) [350/426 (82.2%) versus 305/377 (80.9%), respectively; P = 0.632] populations. Thus, moxifloxacin was non-inferior to TZP–AMC. Bacteriological success rates were high in both treatment arms [moxifloxacin: 432/497 (86.9%) versus TZP–AMC: 370/429 (86.2%), microbiologically valid (MBV) population]. Moxifloxacin was non-inferior to TZP–AMC at TOC in both the MBV and the ITT populations. Both treatments were well tolerated.ConclusionsOnce-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to iv TZP thrice daily followed by oral AMC twice daily in patients with cSSSIs.

Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients

To assess the pharmacokinetics of moxifloxacin in morbidly obese patients. Twelve morbidly obese patients (2 male/10 female, age 25-61 years, weight 98-166 kg, body mass index 43.0-58.2 kg/m(2)) scheduled for gastric bypass surgery were treated with 400 mg of moxifloxacin orally once daily for 3 days and with 400 mg of moxifloxacin intravenously on day 4 (day of surgery). Pharmacokinetic analysis was performed on day 1 and day 4. Specimens of small intestine, greater omentum and subcutaneous adipose tissue were collected intraoperatively 1.8-3.7 h after moxifloxacin infusion. Moxifloxacin concentrations were determined by HPLC. The plasma pharmacokinetics (mean ± SD) was comparable to historical data in normal-weight subjects. Oral bioavailability was 79.6% ± 11.5%. After intravenous administration, plasma clearance was 9.6 ± 2.0 L/h, volume of distribution was 165 ± 30 L and area under the curve was 43.7 ± 11.8 mg·h/L. Linear regression analysis showed the volume of distribution to be better correlated with ideal body weight, lean body weight, fat-free mass or height (R(2) = 0.60-0.67, P = 0.001-0.003) than with total body weight (R(2) = 0.46, P = 0.015). Whereas mean tissue concentrations in small intestine (6.99 ± 2.34 mg/kg) were twice the concomitant plasma concentrations, the concentrations in greater omentum (0.801 ± 0.168 mg/kg) or subcutaneous fat (0.638 ± 0.180 mg/kg) were only one-quarter of those. The pharmacokinetics of moxifloxacin is not significantly affected by morbid obesity. No dose adjustment seems to be necessary in this particular population.

Limited-Sampling Strategies for Therapeutic Drug Monitoring of Moxifloxacin in Patients With Tuberculosis

Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug monitoring is not feasible in most settings. Developing a limited-sampling strategy based on population pharmacokinetics (PK) may help to overcome this problem. Steady-state plasma concentrations after the administration of 400 mg of MFX once daily were determined in 21 patients with TB, using a validated liquid chromatography-tandem mass spectrometry method. A one-compartment population model was generated and crossvalidated. Monte Carlo data simulation (n=1000) was used to calculate limited-sampling strategies. The correlation between predicted MFX AUC0-24h (area under the concentration-time curve 0 to 24 hours) and observed AUC0-24h was investigated by Bland-Altman analysis. Finally, the predictive performance of the final model was tested prospectively using MFX profiles from patients with TB receiving 400, 600, or 800 mg once daily. Median minimum inhibitory concentration of Mycobacterium tuberculosis isolates was 0.25 mg/L (interquartile range: 0.25-0.5 mg/L). The geometric mean AUC0-24h was 24.5 mg·h/L (range: 8.5-72.2 mg·h/L), which resulted in a geometric mean AUC0-24h/minimum inhibitory concentration ratio of 72 (range: 21-321). PK analysis, based on PK profiles of 400 mg of MFX once daily, resulted in a crossvalidated population PK model with the following parameters: apparent clearance (Cl) 18.5±8.6 L/h per 1.85 m, Vd 3.0±0.7 L/kg corrected lean body mass, Ka 1.15±1.16 h, and F was fixed at 1. After the Monte Carlo simulation, the best predicting strategy for MFX AUC0-24h for practical use was based on MFX concentrations 4 and 14 hours postdosing (r=0.90, prediction bias=-1.5%, and root mean square error=15%). MFX AUC0-24h in patients with TB can be predicted with acceptable accuracy for clinical management, using limited sampling. AUC0-24h prediction based on 2 samples, 4 and 14 hours postdose, can be used to individualize treatment.

Efficacy of four different moxifloxacin-based triple therapies for first-line H. pylori treatment

Moxifloxacin has been used in the first-line treatment of Helicobacter pylori infection. The optimal dosage and duration have not been assessed. To evaluate the effectiveness of moxifloxacin, amoxicillin and esomeprazole in four regimens, in previously untreated patients infected by H. pylori. Patients were randomly assigned to: esomeprazole 20 mg b.i.d., amoxicillin 1g b.i.d., and one of each of the four following dosages of moxifloxacin: moxifloxacin 400 mg b.i.d. for 10 days (EAM800x10), moxifloxacin 400 mg b.i.d. for 7 days (EAM800x7), moxifloxacin 400 mg b.i.d. for 5 days (EAM800x5), moxifloxacin 400 mg o.i.d. for 10 days (EAM400x10). Eradication was assessed by the Urea Breath Test (UBT) 2 months following the end of therapy. Ninety-four, 102, 92 and 105 patients were recruited in EAM800x10, EAM800x7, EAM800x5, and EAM400x10 respectively. The eradication rate was for Intention-To-Treat (ITT) and Per Protocol (PP) analyses: EAM800x10 group ITT: 90.4%, PP: 94.4%; EAM800x7 group ITT: 80.3%, PP: 86.3%; EAM800x5 group ITT: 71.4%, PP: 75.2%; EAM400x10 group ITT: 80.0%, PP 84.8%. A statistically significant difference was reached between EAM800x10 vs. EAM800x7 (ITT and PP: P<0.05), and between EAM800x10 vs. EAM800x5 (ITT and PP: P<0.01) and vs. EAM400x10 (ITT: P<0.05; PP: P<0.04). Thirty patients treated unsuccessfully with EAM800x5 and EAM400x10 were re-treated with EAM800x10 with an eradication rate of 86.7% (ITT) and 92.2% (PP). Nineteen patients with positive UBT after EAM800x10 and EAM800x7 underwent a second-line rifabutin-based therapy with an eradication rate of 84.2% (ITT and PP). A triple therapy with 800 mg of moxifloxacin a day for 10 days is more effective than the same treatment for 5 or 7 days and a treatment with 400mg of moxifloxacin a day for 10 days for the first-line eradication of H. pylori infection. The high cost of moxifloxacin-based treatment however, may limit its wide use as first-line treatment of H. pylori infection.

Tissue penetration of moxifloxacin into human gallbladder wall in patients with biliary tract infections

Moxifloxacin, the newest fourth-generation fluoroquinolone, has a broad spectrum of antibacterial activity covering both Gram-positive and Gram-negative aerobic and anaerobic bacteria and is therefore very well suited for the treatment of biliary tract infections. The present study aimed to determine the penetration of moxifloxacin into gallbladder tissue to evaluate its antibiotic potential in this indication. Hospitalized patients with acute cholecystitis received a single, 1 h infusion of 400 mg of moxifloxacin before cholecystectomy. Serum and gallbladder wall tissue samples were collected during surgery, and the moxifloxacin concentrations were measured by HPLC. Sixteen patients (eight men and eight women) were included between January 2007 and April 2008. The time between start of infusion and gallbladder removal ranged from 50 min to 21 h 10 min. The serum concentration at the time of cholecystectomy was between 0.39 and 4.37 mg/L, and the tissue concentration between 1.73 and 17.08 mg/kg. The tissue-to-serum concentration ratio ranged from 1.72 to 6.33. The results show that moxifloxacin penetrates well into gallbladder tissue and is therefore a therapeutic option for biliary tract infection. The highest concentrations in serum and gallbladder tissue were measured shortly after the end of a 1 h infusion. As perioperative prophylaxis, moxifloxacin should therefore be administered 30-60 min before the first surgical incision.